Hyperplastic skin lesions, such as calluses, corns, plantar warts, hyperplastic scarring, genital warts, cutaneous warts, skin tags, and the like are potentially infectious, particularly, genital warts which are a sexually transmitted disease. For hygienic, as well as cosmetic reasons, these warts and skin tags frequently need to be removed.
Hyperplastic skin lesions can result from multiple causes. With psoriasis, the mechanism causing hyperplastic thickening of the skin to form psoriatic plaques is unknown, but appears to be a cell mediated autoimmune process. Areas of the skin subject to excessive repetitive trauma from thermal, chemical or physical means can cause thickening and hypertrophy of the stratum Corneum layer of the epidermis to produce callouses and corns, which are most common on the hands and feet from ill-fitting shoes, or repetitive activities related to work or leisure. Chronic infections can also induce hyperplastic scaring especially in certain individuals predisposed to keloids and other forms of scars that are associated with excessive collagen formation. Other know causes of hyperplasia of the skin are viral infections of the skin that also cause a hyperplasia of the epidermal layers to form pathological lesions such as plantar warts, genital warts, cutaneous warts, skin tags, and the like are potentially infectious, particularly, genital warts which are a sexually transmitted disease. For hygienic, functional, comfort, as well as cosmetic reasons, a safe and painless method for treating these medical conditions associated with hyperplasia of the skin need to be removed/treated.
Any suitable antagonist, generally, of neuronal voltage-dependent Ca.sup.++ channels may be used to reduce or prevent AIDS related vision loss, myelopathy, or dementia. Examples are Nifedipine, mioflazine, flunarizine, bepridil, lidoflazine, Ranolazine, Nisoldipine, Nicardipine, PN200-110, Felodipine, Amlodipine. Preferred calcium channel antagonists include, but are not limited to, the following drugs, of which the most preferred are those that are capable of crossing the blood brain barrier, for example, nimodipine (Miles Pharmaceuticals, West Haven, Conn.) Smith Kline drug no. 9512 (Smith Kline, French Beecham, Philadelphia, Pa.), and diproteverine (Smith, Kline, French-Beecham). Less preferred antagonists are those that are less CNS permeable, for example, verapamil (Calan, G.D. Searle & Co., Chicago, Ill.; Isoptin, Knoll, Whippany, N.J.), nitrendipine, diltiazem (Cardizem, Marion, Kansas City, Mo.), and nifedipine, U.S. Pat. No. 3,485,847, hereby incorporated by reference (Procardia, L Pfizer, NY, N.Y.; Adalat, Miles). Other Ca.sup.2+ channel antagonists which may be useful are mioflazine, flunarizine, bepridil, lidoflazine, CERM-196, R 58735, R-56865, Ranolazine, Nisoldipine, Nicardipine, PN200-110, Felodipine, Amlodipine, R-(−)-202-791, and R-(+) Bay K-8644 (Miles, Bayer), whose chemical formulae are described in Boddeke et al., Trends in Pharmacologic Sciences (1989) 10:397 and Triggle et al., Trends in pharmacologic Sciences (1989) 10:370.
For patients suffering from psoriasis, over 80% will experience hyperplastic thickening of the skin called a psoriatic plaques. Current treatments to control psoriatic plaques involve treatments to suppress the immune response causing the plaques or to us keratolytic agents to soften and remove the plaques. The effectiveness of keratolytic topical agents is that they tend to be irritating not only to the areas of skin affected by the psoriatic process, but also to the healthy surrounding skin which they invariably come in contact with.
Keratolytic agents are also used to treat corns and calluses. Current treatments for corns using keratlytic or skin softening agents also tend to be irritating not only to the areas of skin affected by the psoriatic process, but also to the healthy surrounding skin which they invariably come in contact with. And shaving, abrasive methods also tend to wear through at the thinnest areas of these lesions being treated causing pain and bleeding which prevents there complete removal which helps to ensure there recurrence.
Current treatments for wart removal are surgical excision or repeated application of a toxic chemical to burn and/or dissolve/soften the skin to kill skin cells that are infected. Other methods to kill infected skin tissue involve extreme heating, for example, laser, electro-cautery and the like or extreme cooling such as by liquid nitrogen, or coolant sprays to freeze the lesion and bordering tissues. Unfortunately these methods invariably also destroy healthy skin that is continuous with these viral lesions, resulting in a large area of tissue destruction and a large painful wound that often takes weeks to heal.
Current treatments for wart removal are frequently painful and require prolonged and frequently multiple treatments while having a high rate of recurrence. Wart removal is often ineffective since the pain, discomfort and associated disability often causes patients to terminate their treatment before the virus has been cleared.
Pharmaceutical compositions comprising a calcium channel blocker, particularly verapamil, in combination with a quinoline are known to treat viral infections (U.S. Pat. No. 6,734,192 B1—Keller, Robert H., issued May 11, 2004), particularly HIV. United States Patent Application No. 20040253300, —Easterling, W. Jerry, published Dec. 16, 2004 describes a topical, transdermal medicament for use in treating existing scars comprising: a carrier host agent for facilitating non-invasive, transdermal delivery of a calcium antagonist into scar tissue; a therapeutic dosage of a calcium channel blocker agent suspended in said carrier host agent. The calcium channel blocker is preferably verapamil.
United States Patent Application No. 20050020569, —Easterling. W. Jerry, published Jan. 27, 2005 describes a medicament for use in reducing fibrosis in elastic tissues of the human male comprising: a transdermal carrier compound for facilitating non-invasive, transdermal delivery of calcium channel blocker agents to internal tissues of the human penis; a calcium channel blocker agent dispersed in said carrier means. The calcium channel blocker is preferably verapamil.
United States Patent Application No. 20060216338, —Easterling, W. Jerry, published Sep. 28, 2006 describes a medicament for use in the treatment of tissue disorders involving collagen degeneration, comprising: a carrier compound for facilitation non-invasive, transdermal delivery of calcium channel blocker agents in human recipients; and a calcium channel blocker agent dispersed in said carrier means.
United States Patent Application No. 20080139584, —Kopacki, Matthew H., published Jun. 12, 2008 describes a method for healing a wound, comprising the steps of: topically administering a wound healing composition to a wounded area, wherein the wound healing composition comprises: a first medicament characterized as a calcium channel blocker or pharmaceutically acceptable salts or solvates thereof: a second medicament characterized as a hemorrheologic agent or pharmaceutically acceptable salts or solvates thereof; and a dermal penetrating agent or pharmaceutically acceptable salts or solvates thereof.
Verapamil is a known Ca channel blocker and is a competitive inhibitor of P-glycoprotein, as described by Inoue et al. (1993); Hunter et al. (1993); Hori et al. (1993); Pourtier-Manzanedo et al. (1992); Boesch & Loor (1994); Zacherl et al. (1994); Shirai et al. (1991); Morris et al. (1991); Muller et al. (1994); and Miyamoto et al. (1992). Thalhammer et al. (1994) showed that P-glycoprotein-mediated transport of the cationic dye, acridine orange, across the bile canaliculi was inhibited by cyclosporine A and verapamil.
The ATP-15 dependent transport of amphiphilic cations across the hepatocyte canalicular membrane by p-glycoprotein was also studied by Muller et al. (1994). Transport of permanently charged amphiphilic cations was inhibited by verapamil, quinidine and daunorubicin (an antibiotic). Bear (1994) showed that verapamil, colchicine, vinblastine daunomycin and (50 microM) blocked an outwardly-rectifying chloride channel that was proposed to be associated with p-glycoprotein expression. Obi et al. (1992) used the calcium-channel blocker, verapamil, with adriamycin in chemotherapy for superficial bladder cancer.
Verapamil hydrochloride is benzeneacetonitrile α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-methylamino]propyl]-3,4-dimethoxy-α-(1-methyl-ethyl) hydrochloride; also termed CALAN™ and ISOPTIN™, and available from Searle, Knoll and Parke-Davis.
However, none of the prior art discloses the use of compositions comprising a calcium channel or a calmodulin blocker by topical application for the elimination of hyperplastic skin lesions of the dermis and epidermis, such as plantar warts, hyperplastic scarring, genital warts, cutaneous warts, skin tags.
Thus, there is still a serious need for a pharmaceutical treatment of aforesaid warts and the like.